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Topline data from the pivotal INFRONT-3 Phase 3 clinical trial of latozinemab in FTD-GRN expected by Q4 2025 Anticipate completing enrollment in the PROGRESS-AD Phase 2 clinical trial of AL101/GSK4527226 in participants with early Alzheimer’s disease by mid-2025 Applying Alector Brain Carrier to advance therapeutic candidates, including those targeting amyloid beta and replacing GCase $413.4 million in cash, cash equivalents and investments provide runway through 2026 Management to host conference call and webcast today at 4:30 p.m. ET/1:30 p.m. PT SOUTH SAN FRANCISCO, Calif., Feb. 26, 2025 (GLOBE NEWSWIRE) -- Alector, Inc. (Nasdaq: ALEC), a late-stage clinical biotechnology company focused on developing therapies to counteract the devastating progression of neurodegeneration, today reported fourth quarter and full year 2024 financial results and recent portfolio and business updates. As of December 31, 2024, Alector’s cash, cash equivalents and investments totaled $413.4 million. “Alector is entering a potentially transformative period for the company, as we continue to advance our clinical programs toward key milestones while also driving the development of our wholly owned, early-stage pipeline,” said Arnon Rosenthal, Ph.D., Chief Executive Officer of Alector. “We look forward to reporting topline data from the pivotal INFRONT-3 Phase 3 trial of latozinemab targeting frontotemporal dementia with a granulin gene mutation by the fourth quarter. Additionally, we expect to complete enrollment in the PROGRESS-AD Phase 2 trial of AL101/GSK4527226 in participants with early Alzheimer’s disease by mid-2025. With our broad and diverse portfolio of genetically validated drug candidates for the treatment of neurodegenerative diseases, backed by a strong financial position that will fund operations through 2026, Alector is well-positioned to advance our mission to deliver transformative therapies for patients with neurodegenerative brain disorders.” Sara Kenkare-Mitra, Ph.D., President and Head of Research and Development at Alector, added, “We are making significant progress in advancing Alector’s preclinical and research pipeline. By leveraging our expertise in neuroscience and drug discovery, and selectively applying our proprietary Alector Brain Carrier technology platform, we are able to enhance brain delivery and biodistribution of therapeutic cargo to potentially improve safety and efficacy. We are currently selecting lead candidates for two programs, ADP037-ABC, targeting amyloid beta, and ADP050-ABC, replacing GCase. We aim to advance these programs toward IND-enabling studies later this year, with plans to enter the clinic in 2026.” Recent Clinical Updates Progranulin Programs (latozinemab (AL001) and AL101/GSK4527226) Being Developed in Collaboration with GSK Latozinemab The pivotal, randomized, double-blind, placebo-controlled INFRONT-3 Phase 3 clinical trial of latozinemab targeting frontotemporal dementia with a granulin gene mutation (FTD-GRN) is ongoing. Topline data are anticipated by the fourth quarter of 2025. Latozinemab is a novel investigational human monoclonal antibody (mAb) designed to block and downregulate the sortilin receptor to elevate the level of progranulin (PGRN) in the brain. It has been granted Orphan Drug, Breakthrough Therapy and Fast Track designations, and the company believes it is the most advanced PGRN-elevating candidate in development for this condition. AL101/GSK4527226 PROGRESS-AD, a global, randomized, double-blind, placebo-controlled Phase 2 clinical trial evaluating AL101/GSK4527226 in early Alzheimer’s disease (AD) continues to enroll well, with substantial progress toward its target enrollment of 282 participants. Alector and GSK plan to complete trial enrollment by mid-2025. AL101/GSK4527226 is an investigational human mAb designed to block and downregulate the sortilin receptor to elevate the level of PGRN in the brain in a manner that is similar to investigational latozinemab but with different pharmacokinetic and pharmacodynamic properties, making it suitable for the potential treatment of more prevalent neurodegenerative diseases. Preclinical and Research Pipeline Alector is advancing a preclinical and early research pipeline focused on removing toxic proteins, replacing deficient proteins, and restoring immune and nerve cell function. Leveraging its deep expertise in drug development and proprietary technologies, including protein engineering, antibody discovery, and its Alector Brain Carrier (ABC) platform for blood-brain barrier transport, the company is progressing a curated portfolio of programs targeting genetically validated disease mechanisms. This approach has led to a suite of innovative programs with the potential to make a significant impact on neurodegeneration. ADP037-ABC is a proprietary anti-amyloid beta (Aβ) antibody paired with the company’s ABC for the treatment of AD. It is designed to remove brain Aβ plaques, with the potential to reduce the incidence and/or severity of amyloid-related imaging abnormalities (ARIA) and enable subcutaneous delivery. It targets a validated epitope, specific to brain Aβ plaques, combined with an optimized antibody constant region to enhance phagocytosis of Aβ plaques. By leveraging ABC technology, ADP037-ABC aims to clear Aβ efficiently, thereby reducing plaque accumulation and potentially slowing disease progression while minimizing ARIA. ADP050-ABC is a GCase replacement therapy paired with the company’s proprietary ABC for GBA gene mutation carriers with Parkinson’s disease (PD) and Lewy body dementia. In these patients, mutations in the GBA gene lead to deficient GCase activity. ADP050-ABC uses Alector-engineered GCase, which is proprietary and has been designed to have a longer half-life and to break down glucocerebroside, a lipid that accumulates in neurons and contributes to neurodegeneration. This mechanism aims to reduce cellular dysfunction and slow disease progression. ADP056 is a Reelin modulator designed to block tau pathology and promote synaptic function in AD. Reelin, a large, secreted protein, regulates neuronal function and tau accumulation. Gain-of-function Reelin variants protect against familial AD through a mechanism that appears to uncouple amyloid and tau pathology. ADP056 is designed to mimic these protective effects of the Reelin mutation. ADP063-ABC and ADP064-ABC are therapeutic candidates paired with the company’s proprietary ABC that target tau pathology in AD through distinct approaches. First, ADP063-ABC will focus on combining a proprietary anti-tau antibody directed to a validated tau epitope with ABC and an optimized antibody constant region. It is designed to block the spread of tau aggregates and has the potential for subcutaneous delivery. Second, ADP064-ABC will focus on using an anti-tau siRNA combined with ABC, which aims to prevent the synthesis of the tau mRNA and protein. Both approaches seek to leverage a highly brain-penetrant approach to remove toxic tau and potentially slow cognitive decline in AD. In December 2024, Alector and co-recipient University of Luxembourg were awarded a $1.7 million grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) for collaborative research on glycoprotein nonmetastatic melanoma protein B (GPNMB), a PD target. Alector plans to hold an educational webinar in the second quarter of 2025 to present additional preclinical data on the company’s anti-amyloid beta and GCase programs, as well as advancements in ABC. TREM2 Program (AL002) On April 5, 2025, Alector plans to present the results from the INVOKE-2 Phase 2 clinical trial, which evaluated the safety and efficacy of AL002, a TREM2 agonist, in individuals with early AD, during an oral presentation at the AD/PD™ 2025 International Conference on Alzheimer’s and Parkinson’s Diseases, taking place in Vienna, Austria. While the trial did not meet its primary endpoint, Alector remains committed to advancing the understanding of AD pathophysiology and the development of effective therapeutics for the disease. Fourth Quarter 2024 Financial Results Revenue. Collaboration revenue for the quarter ended December 31, 2024, was $54.2 million, compared to $15.2 million for the same period in 2023. Collaboration revenue for the year ended December 31, 2024, was $100.6 million, compared to $97.1 million for the same period in 2023. The increase in year-over-year collaborative revenue was primarily due to an increase in revenue recognized for the AL002 and latozinemab programs. Collaboration revenue under the AbbVie Agreement was fully recognized as of December 31, 2024. R&D Expenses. Total research and development expenses for the quarter ended December 31, 2024, were $46.5 million, compared to $47.7 million for the quarter ended December 31, 2023. Total research and development expenses for the year ended December 31, 2024, were $185.9 million compared to $192.1 million for the same period in 2023. The decrease in year-over-year R&D expenses was mainly due to the Company’s strategy to prioritize selected programs. G&A Expenses. Total general and administrative expenses for the quarter ended December 31, 2024, were $15.0 million compared to $14.9 million for the quarter ended December 31, 2023. Total general and administrative expenses for the year ended December 31, 2024, were $59.6 million compared to $56.7 million for the year ended December 31, 2023. The increase in year-over-year G&A expenses is primarily due to the impairment of the right-of-use asset and the leasehold improvements as the Company approved a plan to transition operations from our laboratory and offices in Newark, California to our South San Francisco Headquarters. Net Loss. For the quarter ended December 31, 2024, Alector reported a net loss of $2.1 million, or $0.02 net loss per share, compared to a net loss of $41.4 million, or $0.49 net loss per share, for the same period in 2023. For the year ended December 31, 2024, Alector reported a net loss of $119.0 million or $1.23 net loss per share, compared to a net loss of $130.4 million or $1.56 net loss per share, for the same period in 2023. Cash Position. Cash, cash equivalents, and investments were $413.4 million as of December 31, 2024. Management expects that this will be sufficient to fund current operations through 2026. 2025 Guidance. Management anticipates, for the year ending 2025, collaboration revenue to be between $5 million and $15 million, total research and development expenses to be between $175 million and $185 million, and total general and administrative expenses to be between $55 million and $65 million. Fourth Quarter and Full Year 2024 Conference Call Alector’s management team will host a conference call to discuss Alector’s results for the fourth quarter and full year 2024, as well as provide a business update. The conference call will be webcast and accessible via the investor relations section of Alector’s website at www.alector.com. To access the call, please use the following information: Date: Wednesday, February 26, 2025 Time: 4:30 p.m. ET, 1:30 p.m. PT The event will be webcast live under the investor relations section of Alector’s website at https://investors.alector.com/events-and-presentations/events and following the event a replay will be archived there for 30 days. Interested parties participating by phone will need to register using this online form. After registering for dial-in details, all phone participants will receive an auto-generated e-mail containing a link to the dial-in number along with a personal PIN number to use to access the event by phone. About Alector Alector is a late-stage clinical biotechnology company focused on developing therapies to counteract the devastating progression of neurodegenerative diseases. Leveraging the principles of genetics, immunology and neuroscience, the company is advancing a portfolio of genetically validated programs that aim to remove toxic proteins, replace missing proteins, and restore immune and nerve cell function. Supported by biomarkers, Alector’s product candidates seek to treat a range of indications, including frontotemporal dementia, Alzheimer’s disease, Parkinson's disease, and Lewy body dementia. The company is also developing Alector Brain Carrier (ABC), a proprietary blood-brain barrier platform, which is being selectively applied to its next-generation product candidates and research pipeline. ABC aims to enhance the delivery of therapeutics, achieve deeper brain penetration and efficacy at lower doses, and ultimately improve patient outcomes while reducing costs. Alector is headquartered in South San Francisco, California. For more information, please visit www.alector.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements in this press release include, but are not limited to, statements regarding our business plans, business strategy, product candidates, blood-brain barrier technology platform, research and preclinical pipeline, planned and ongoing preclinical studies and clinical trials, anticipated timing of and detail regarding release of data for INFRONT-3, expected milestones, expectations of our collaborations, expectations of our interactions with regulatory authorities, and financial and cash guidance. Such statements are subject to numerous risks and uncertainties, including but not limited to risks and uncertainties as set forth in Alector’s Quarterly Report on Form 10-K filed for 2024, with the Securities and Exchange Commission (“SEC”), as well as the other documents Alector files from time to time with the SEC. These documents contain and identify important factors that could cause the actual results for Alector to differ materially from those contained in Alector’s forward-looking statements. Any forward-looking statements contained in this press release speak only as of the date hereof, and Alector specifically disclaims any obligation to update any forward-looking statement, except as required by law. Alector Contacts: Alector Katie Hogan 202-549-0557 katie.hogan@alector.com Argot Partners (media) David Rosen (212) 600-1494 alector@argotpartners.com Argot Partners (investors) Laura Perry 212-600-1902 alector@argotpartners.com Source: Alector, Inc.

Continue to advance preclinical and research pipeline, including key programs selectively combined with Alector Brain Carrier, enhancing the company’s commitment to developing genetically-validated therapies for neurodegeneration Topline data from the pivotal INFRONT-3 Phase 3 clinical trial of latozinemab in FTD-GRN expected by Q4 2025 Completion of enrollment in the PROGRESS-AD Phase 2 trial of AL101/GSK4527226 for early Alzheimer’s disease anticipated in mid-2025, with approximately 75% target recruitment achieved $457.2 million in cash, cash equivalents and investments as of September 30, 2024, expected to fund operations through 2026 SOUTH SAN FRANCISCO, Calif., Jan. 13, 2025 (GLOBE NEWSWIRE) -- Alector, Inc. (Nasdaq: ALEC), a late-stage clinical biotechnology company focused on developing therapies to counteract the devastating progression of neurodegeneration, today highlighted recent progress and strategic priorities for 2025. "Alector remains steadfast in our mission to deliver transformative treatments for neurodegenerative diseases. As we begin 2025, we are focused on the significant milestones ahead,” said Arnon Rosenthal, Ph.D., Chief Executive Officer of Alector. "We look forward to the anticipated topline data readout for the pivotal INFRONT-3 Phase 3 trial of latozinemab in frontotemporal dementia with a granulin gene mutation, expected by the fourth quarter of 2025. Latozinemab has been granted Orphan Drug, Breakthrough Therapy, and Fast Track designations, and the upcoming data readout will be an important milestone for our program. The Phase 2 PROGRESS-AD trial of AL101/GSK4527226 is also advancing well, with approximately 75% of participants enrolled, and we anticipate reaching full enrollment in mid-2025. In parallel, we continue to advance our preclinical and research pipeline with key programs, including ADP037-ABC, a brain-penetrant anti-amyloid beta antibody for Alzheimer’s disease; ADP050-ABC, a brain-penetrant GCase replacement therapy for Parkinson’s disease and Lewy body dementia; as well as ADP063-ABC and ADP064-ABC, brain-penetrant, tau-blocking therapeutic candidates. These programs leverage our Alector Brain Carrier technology platform, which aims to enhance therapeutic delivery to the brain. This could potentially lead to efficacy at lower doses, more convenient subcutaneous delivery and expanded therapeutic windows, as well as lower treatment costs. Additionally, ADP056, our reelin modulator, is designed to block tau pathology and promote synaptic function in Alzheimer's disease. Collectively, our programs support our broad and diverse strategy for advancing investigational treatments for neurodegenerative diseases. With our strong cash position, we are well-poised to continue advancing our clinical and preclinical pipeline.” Recent Progress and 2025 Strategic Priorities: Progranulin Programs (latozinemab (AL001) and AL101/GSK4527226) Being Developed in Collaboration with GSK Latozinemab The pivotal, randomized, double-blind, placebo-controlled INFRONT-3 Phase 3 clinical trial of latozinemab targeting frontotemporal dementia with a granulin gene mutation (FTD-GRN) is ongoing. Topline data are anticipated by the fourth quarter of 2025. Latozinemab is a novel investigational human monoclonal antibody (mAb) designed to increase progranulin (PGRN) levels in the brain by inhibiting sortilin. It was granted U.S. Food and Drug Administration Breakthrough Therapy Designation for FTD-GRN in early 2024, and the company believes it is the most advanced PGRN-elevating candidate in development for this condition. Heterozygous loss-of-function mutations in the GRN gene cause FTD due to PGRN haploinsufficiency.1,2 Latozinemab is a novel investigational human monoclonal antibody (mAb) designed to increase progranulin (PGRN) levels in the brain by inhibiting sortilin. It was granted U.S. Food and Drug Administration Breakthrough Therapy Designation for FTD-GRN in early 2024, and the company believes it is the most advanced PGRN-elevating candidate in development for this condition. Heterozygous loss-of-function mutations in the GRN gene cause FTD due to PGRN haploinsufficiency.1,2 AL101/GSK4527226 PROGRESS-AD, a global, randomized, double-blind, placebo-controlled Phase 2 clinical trial evaluating AL101/GSK4527226 in early Alzheimer’s disease (AD), has reached approximately 75% of its target enrollment of 282 participants. Alector and GSK plan to complete trial enrollment in mid-2025. ​AL101/GSK4527226 is an investigational human mAb designed to block and downregulate the sortilin receptor to elevate the level of PGRN in the brain in a manner that is similar to investigational latozinemab but with different pharmacokinetic and pharmacodynamic properties, making it suitable for the potential treatment of more prevalent neurodegenerative diseases. Modest reduction in the levels of PGRN due to GRN gene mutations has been shown to be associated with an increased risk of developing AD. Conversely, an elevation of PGRN has been shown to be protective in animal models of AD.3 ​AL101/GSK4527226 is an investigational human mAb designed to block and downregulate the sortilin receptor to elevate the level of PGRN in the brain in a manner that is similar to investigational latozinemab but with different pharmacokinetic and pharmacodynamic properties, making it suitable for the potential treatment of more prevalent neurodegenerative diseases. Modest reduction in the levels of PGRN due to GRN gene mutations has been shown to be associated with an increased risk of developing AD. Conversely, an elevation of PGRN has been shown to be protective in animal models of AD.3 Preclinical and Research Pipeline Alector continues to advance its preclinical and research pipeline by leveraging its expertise in neuroscience and selectively applying its proprietary blood-brain barrier technology platform, Alector Brain Carrier (ABC). This strategic approach positions the company to develop therapeutic candidates for a range of neurodegenerative diseases. ADP037-ABC is a proprietary anti-amyloid beta (Aβ) antibody paired with the company’s ABC for the treatment of AD. It is designed to remove brain amyloid plaques, with the potential to reduce the risk of amyloid-related imaging abnormalities (ARIA) and enable subcutaneous delivery. It targets a validated epitope specific to brain amyloid plaques, combined with an optimized antibody constant region to enhance phagocytosis of Aβ plaques. By leveraging ABC technology, ADP037-ABC aims to clear Aβ efficiently, thereby reducing plaque accumulation and slowing disease progression while minimizing ARIA. ADP050-ABC is a GCase replacement therapy paired with the company’s proprietary ABC for GBA gene mutation carriers with Parkinson’s disease (PD) and Lewy body dementia. In these patients, mutations in the GBA gene lead to deficient GCase activity. ADP050-ABC uses Alector-engineered GCase, which has been designed to have a longer half-life and to break down glucocerebroside, a lipid that accumulates in neurons and contributes to neurodegeneration. This mechanism aims to reduce cellular dysfunction and slow disease progression. ADP056 is a reelin modulator designed to block tau pathology and promote synaptic function in AD. Reelin, a large, secreted protein, regulates neuronal function and tau accumulation. Gain-of-function reelin variants protect against familial AD through a mechanism that appears to uncouple amyloid and tau pathology. ADP056 is designed to mimic and exceed these protective effects of the reelin mutation. ADP063-ABC and ADP064-ABC are therapeutic candidates paired with ABC that target tau pathology in AD through distinct approaches. ADP063-ABC combines a proprietary anti-tau antibody with ABC and an optimized antibody constant region. It is designed to block the spread of tau aggregates and has the potential for subcutaneous delivery. ADP064-ABC uses an anti-tau siRNA, which aims to prevent the synthesis of the tau mRNA and protein. Both approaches seek to potentially slow cognitive decline in AD. In December 2024, Alector and co-recipient University of Luxembourg were awarded a $1.7 million grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) for collaborative research on GPNMB, a PD target. The research will be used by Alector to advance its ADP027-ABC program, which targets GPNMB for the potential treatment of PD. ADP037-ABC is a proprietary anti-amyloid beta (Aβ) antibody paired with the company’s ABC for the treatment of AD. It is designed to remove brain amyloid plaques, with the potential to reduce the risk of amyloid-related imaging abnormalities (ARIA) and enable subcutaneous delivery. It targets a validated epitope specific to brain amyloid plaques, combined with an optimized antibody constant region to enhance phagocytosis of Aβ plaques. By leveraging ABC technology, ADP037-ABC aims to clear Aβ efficiently, thereby reducing plaque accumulation and slowing disease progression while minimizing ARIA. ADP050-ABC is a GCase replacement therapy paired with the company’s proprietary ABC for GBA gene mutation carriers with Parkinson’s disease (PD) and Lewy body dementia. In these patients, mutations in the GBA gene lead to deficient GCase activity. ADP050-ABC uses Alector-engineered GCase, which has been designed to have a longer half-life and to break down glucocerebroside, a lipid that accumulates in neurons and contributes to neurodegeneration. This mechanism aims to reduce cellular dysfunction and slow disease progression. ADP056 is a reelin modulator designed to block tau pathology and promote synaptic function in AD. Reelin, a large, secreted protein, regulates neuronal function and tau accumulation. Gain-of-function reelin variants protect against familial AD through a mechanism that appears to uncouple amyloid and tau pathology. ADP056 is designed to mimic and exceed these protective effects of the reelin mutation. ADP063-ABC and ADP064-ABC are therapeutic candidates paired with ABC that target tau pathology in AD through distinct approaches. ADP063-ABC combines a proprietary anti-tau antibody with ABC and an optimized antibody constant region. It is designed to block the spread of tau aggregates and has the potential for subcutaneous delivery. ADP064-ABC uses an anti-tau siRNA, which aims to prevent the synthesis of the tau mRNA and protein. Both approaches seek to potentially slow cognitive decline in AD. As of September 30, 2024, Alector had $457.2 million in cash, cash equivalents, and investments, which the company continues to expect will provide runway through 2026. Alector plans to provide guidance for 2025 during its fourth-quarter and full-year earnings conference call. About Alector Alector is a late-stage clinical biotechnology company focused on developing therapies to counteract the devastating progression of neurodegenerative diseases. Leveraging the principles of genetics, immunology and neuroscience, the company is advancing a portfolio of genetically-validated programs that aim to remove toxic proteins, replace deficient proteins, and restore immune and nerve cell function. Supported by biomarkers, Alector’s product candidates seek to treat a range of indications, including frontotemporal dementia, Alzheimer’s disease, Parkinson's disease, and Lewy body dementia. The company is also developing Alector Brain Carrier (ABC), a proprietary blood-brain barrier platform, which is being selectively applied to its next-generation product candidates and research pipeline. ABC aims to enhance the delivery of therapeutics, achieve deeper brain penetration and efficacy at lower doses, and ultimately improve patient outcomes while reducing costs. Alector is headquartered in South San Francisco, California. For more information, please visit www.alector.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements in this press release include, but are not limited to, statements regarding our business plans, business strategy, product candidates, blood-brain barrier technology platform, planned and ongoing preclinical studies and clinical trials, anticipated timing of and detail regarding release of data for INFRONT-3, expected milestones, expectations of our collaborations, expectations of our interactions with regulatory authorities, and financial and cash guidance. Such statements are subject to numerous risks and uncertainties, including but not limited to risks and uncertainties as set forth in Alector’s Quarterly Report on Form 10-Q filed on November 6, 2024, with the Securities and Exchange Commission (“SEC”), as well as the other documents Alector files from time to time with the SEC. These documents contain and identify important factors that could cause the actual results for Alector to differ materially from those contained in Alector’s forward-looking statements. Any forward-looking statements contained in this press release speak only as of the date hereof, and Alector specifically disclaims any obligation to update any forward-looking statement, except as required by law. REFERENCES Alector Contacts: Alector Katie Hogan 202-549-0557 katie.hogan@alector.com Argot Partners (media) David Rosen (212) 600-1494 alector@argotpartners.com Argot Partners (investors) Laura Perry 212-600-1902 alector@argotpartners.com Source: Alector, Inc.

MONDAY, May 15, 2023 -- Researchers have discovered a genetic mutation that should actively protect people from Alzheimer’s, thanks to a man belonging to a Colombian family known to be susceptible to the degenerative brain disease. Based on his family's genetics, this unnamed patient should have started showing signs of Alzheimer’s in his 40s. “They start getting impaired at age 44. By 49, they have dementia, By 60, they are dead,” said co-researcher Dr. Joseph Arboleda-Velasquez , an associate scientist at Mass Eye and Ear, a research institute with Mass General Brigham in Boston. But this man showed no signs of cognitive decline by age 67, Arboleda-Velasquez said. “The patient was studied and went through a battery of cognitive tests. At 67, he was fine,” he said. “He should have been dead by then, but for him, it hadn't even started. That is just remarkable.” The man was diagnosed with mild cognitive impairment at age 70. Imaging scans taken at 73 showed his brain was riddled with the amyloid plaques and tau tangles that are hallmarks of Alzheimer’s. He died of pneumonia at age 74, having progressed to moderate dementia, researchers said. Critical for protection So what protected his brain from the ravages of Alzheimer’s? Research conducted after his death revealed that he carried a specific mutation in a gene that regulates reelin, a protein that serves a pivotal role in brain cell development. The mutation enhances the function of reelin, and reelin naturally hampers the process that causes tau proteins to stick together in tangles and impede brain function, Arboleda-Velasquez said. “This mutation in reelin makes reelin work better, what we call a gain of function,” he said. “You have a situation where the mutation increases the function of a protein that already has a beneficial effect.” Specifically, the reelin mutation appeared to have diminished the number of tau tangles that accumulated in the man’s entorhinal cortex, an area of the brain that serves a critical role in memory and learning. “This case indicates that the entorhinal region may represent a tiny target that’s critical for protection against dementia,” senior researcher Yakeel Quiroz , director of the Familial Dementia Neuroimaging Lab at Mass General Hospital, said in a hospital news release. The identification of this reelin gene and the brain region it most benefits should break open a new front on the war against Alzheimer’s, alongside ongoing efforts to prevent the plaques of amyloid beta protein that are another trait of the brain disease, Arboleda-Velasquez said. “I would say 95% of the efforts for therapeutic development have focused on amyloid, and maybe 4% or 5% have focused on tau,” he said. “This shows us that there is this other pathway that doesn't really have to do much with amyloid.” Focus on a family This new finding stems from ongoing research of an extended family of 6,000 people in Colombia who carry the “Paisa” mutation, a genetic variant known to significantly increase risk of early-onset Alzheimer’s. Researchers have been following this family for three decades, and in 2019, their efforts uncovered one protective genetic mutation in a woman who remained unimpaired until her 70s. That woman carried two copies of a variant called APOE3-Christchurch, which also appears to inhibit the development of tau tangles. The apolipoprotein E (APOE) gene is known to influence genetic risk for Alzheimer’s. The man didn’t carry APOE3-Christchurch, so researchers went looking for another genetic factor that could explain his resilience. The reelin mutation “would be really the second major protective factor found within this family of individuals where there’s a mutation associated with young onset Alzheimer’s disease,” said Dr. Vijay Ramanan , a neurologist with the Mayo Clinic in Rochester, Mass. The newly discovered mutation appears to inhibit a process called phosphorylation, which induces a structural change that causes naturally occurring tau proteins to tangle with other threads of tau, Arboleda-Velasquez said. The tau tangles that occur in the brains of Alzheimer’s patients are highly phosphorylated. Arboleda-Velasquez is confident that reelin itself could be administered as a therapy to block at least one pathway by which Alzheimer’s progresses. “It's very clear that the mutation offered a gain of function. If that is so, that means more reelin is better. More reelin should do it,” he said. “It’s just a matter of how we’re going to do it, how we are going to give it to patients. I think it has tremendous promise.” Targeting tau Ramanan, who wasn't involved with the new research, agreed that the findings should spur research into tau as a culprit in Alzheimer’s. “We know that there are multiple factors involved in Alzheimer's disease. It is a complex disease and multiple pathways are contributory,” Ramanan said. “But the accumulation of tau in the brain is very tightly connected to the character of symptoms that folks experience and the timing when they experience those symptoms." From that standpoint alone, he said, it makes great sense to think about targeting tau as a treatment. “When you see a genetic factor with a relationship potentially to modifying tau burden as having the ability to also protect against the development of dementia in a familial situation where there's incredibly high risk, it really sort of adds fuel to that direction of research,” Ramanan added. The new study was published May 15 in the journal Nature Medicine . Sources Joseph Arboleda-Velasquez, MD, PhD, associate scientist, Mass Eye and Ear, Boston, and associate professor, ophthalmology, Harvard Medical School, Boston Vijay Ramanan, MD, PhD, neurologist, Mayo Clinic, Rochester, Minn. Mass General Brigham, news release, May 15, 2023 Nature Medicine , May 15, 2023 Posted May 2023