Cognition

Adult hippocampal neurogenesis (AHN) is the process by which new neurons arise from neural stem and progenitor cells in the subgranular zone of the hippocampal dentate gyrus (DG) and integrate into granule-cell circuits involved in pattern separation, episodic memory encoding, and mood regulation. In rodents, newly born DG granule cells mature over roughly four to eight weeks, regulated by Wnt, Notch, and BDNF, before becoming synaptically incorporated. Whether AHN persists in adult humans remains one of the most actively debated questions in neuroscience. Two widely cited 2018 post-mortem studies reached opposite conclusions: Sorrells et al. (Nature 2018) found immature-neuron markers (DCX, PSA-NCAM) undetectable in human DG beyond early childhood, whereas Boldrini et al. (Cell Stem Cell 2018), using optimised tissue fixation, reported thousands of DCX-positive neuroblasts in donors up to 79 years old. Post-mortem interval, fixation duration, and antibody sensitivity are the leading explanation for the discrepancy. Radiocarbon birth-dating independently estimated approximately 1.75% annual turnover of DG neurons in adult humans (Spalding et al., Cell 2013). Aerobic exercise reliably elevates hippocampal BDNF and increases DG neurogenesis in rodents; whether the same causal link holds in adult humans is plausible but not yet demonstrated causally, making exercise-promoted AHN an inferential mechanism for associations between physical activity, hippocampal volume preservation, and delayed cognitive decline.

Amyloid-β (Aβ) is a family of peptides of 36–43 amino acids cleaved from the amyloid precursor protein (APP) by β- and γ-secretase; the 42-residue form (Aβ42) is especially prone to misfolding and aggregation into soluble oligomers and insoluble amyloid plaques. Aβ42 plaques are a defining histopathological feature of Alzheimer's disease, detectable by PET imaging or CSF assay years before clinical symptoms. The amyloid cascade hypothesis proposes Aβ accumulation as an upstream initiator of Alzheimer's pathology, but whether plaques themselves are the primary toxic species or an epiphenomenon remains debated — soluble oligomers rather than fibrillar plaques are now widely regarded as the most neurotoxic form. Anti-amyloid monoclonal antibodies lecanemab (FDA approval 2023, EMA approval 2025) and donanemab (FDA approval 2024) have completed phase-3 trials and received regulatory approval, showing modest but statistically significant slowing of cognitive decline with substantial plaque clearance, lending qualified support to the cascade hypothesis. Aducanumab (Aduhelm) received accelerated FDA approval in 2021 but was withdrawn by Biogen in January 2024 due to commercial failure; it never received EMA approval.

Amyloid precursor protein is a type I transmembrane glycoprotein encoded on chromosome 21 and expressed widely in the central nervous system. In the non-amyloidogenic pathway alpha-secretase cleaves APP within the amyloid-beta sequence; in the amyloidogenic pathway beta-secretase (BACE1) then gamma-secretase release amyloid-beta peptides of 38 to 43 residues, of which Abeta42 is the most aggregation-prone and central to plaque formation. Pathogenic missense mutations in APP and duplications of the APP locus cause autosomal-dominant early-onset Alzheimer disease; trisomy 21 (Down syndrome) produces a third APP copy and near-universal Alzheimer pathology by midlife. The Icelandic A673T variant lowers BACE1 cleavage and protects against Alzheimer disease, providing genetic support for the amyloid hypothesis. The amyloid hypothesis gained renewed clinical relevance with the approval of anti-amyloid monoclonal antibodies — lecanemab (FDA 2023, EU 2025) and donanemab (FDA 2024, EU 2025) — for early symptomatic Alzheimer disease.

BDNF is a growth-factor protein that supports neuronal survival, synapse formation, and — at least in animal models — adult hippocampal neurogenesis (its extent in adult humans remains debated). Levels rise with aerobic exercise and quality sleep; effects of intermittent fasting are well-established in rodents but less clear in humans, and levels fall under chronic stress and depression. In longevity research, lower BDNF is associated with depression and Alzheimer's risk, linking lifestyle to memory and mood regulation.

The blood-brain barrier (BBB) is a highly selective neurovascular interface formed by specialised endothelial cells lining cerebral capillaries, reinforced by tight-junction proteins, astrocytic endfeet, and pericytes (mural cells that wrap around capillary walls and regulate permeability). Together these elements constitute the neurovascular unit, which controls the passage of molecules between blood and brain parenchyma, maintains ion homeostasis, and excludes pathogens and blood-derived neurotoxins. With advancing age the BBB undergoes progressive structural and functional deterioration: pericyte loss, reduced tight-junction protein expression, and endothelial dysfunction increase paracellular permeability, allowing albumin, fibrinogen, and other plasma proteins to leak into the neuropil. A human imaging study by Montagne et al. (2015, Neuron) using dynamic contrast-enhanced MRI demonstrated that BBB breakdown in the hippocampus — a region central to episodic memory — occurs early in normal aging and worsens in proportion to the degree of mild cognitive impairment, with pericyte injury (indexed by elevated cerebrospinal-fluid PDGFR-β) as the correlating biomarker. A 2024 review in the Journal of Cerebral Blood Flow & Metabolism (Cao et al.) catalogues age-related BBB changes across all cellular components and concludes that oxidative-stress-driven pericyte apoptosis and neuroinflammatory signalling are the most mechanistically consistent drivers identified across human and rodent data, though direct causal evidence in humans remains limited to biomarker associations rather than intervention studies.

Cerebral blood flow (CBF) is the volume of blood delivered per unit time, expressed in mL per 100 g per minute, regulated via autoregulation, arterial CO₂ sensitivity, and neurovascular coupling. In neurovascular coupling, neuronal activity triggers vasoactive agent release from neurons and astrocytes — nitric oxide, prostaglandins, potassium — relaxing arteriolar smooth muscle and capillary pericytes to raise perfusion at sites of metabolic demand. Resting CBF declines roughly 5% per decade, driven by rising cerebrovascular resistance, arterial stiffening, and impaired endothelial NO synthesis; pulsatility increases after midlife and correlates with white matter hyperintensity burden (Tarumi and Zhang, 2017). Chronic hypoperfusion reduces oxygen and glucose delivery, promotes capillary stalling, and reinforces amyloid-β accumulation — impaired clearance worsens vascular dysfunction, which deepens hypoperfusion, a bidirectional cycle in Alzheimer and vascular dementia (Toth et al., 2017). In a one-year RCT (n = 56 older adults), aerobic training raised CBF 5 ± 7% versus 0 ± 5% in controls (p = 0.007), reduced cerebrovascular resistance 7%, and correlated with improved recall (r = −0.49; Tomoto et al., 2023). A 2022 systematic review found consistent associations between exercise-induced CBF gains and cognition, though protocol heterogeneity limits effect estimates (Renke et al., 2022). Methods include arterial spin labelling MRI, transcranial Doppler, and phase-contrast MRI. Whether hypoperfusion causally precedes dementia or co-occurs with it remains unresolved.

Cerebral small vessel disease (CSVD) encompasses a spectrum of pathological changes affecting the perforating arteries, arterioles, capillaries and venules of the brain, resulting in a characteristic constellation of neuroimaging findings: white matter hyperintensities, lacunar infarcts, enlarged perivascular spaces, microbleeds and cortical superficial siderosis. Hypertension is the dominant modifiable risk factor; additional contributors include diabetes, dyslipidaemia, smoking and genetic variants such as NOTCH3 mutations in CADASIL. CSVD accounts for approximately 20% of all strokes (about 25% of ischemic strokes, predominantly lacunar) and is the most common cause of vascular cognitive impairment, with cumulative lesion burden correlating with executive dysfunction, gait disturbance, depression and progression to vascular dementia. Currently there is no disease-modifying pharmacotherapy specific to CSVD; blood pressure control remains the most robustly evidence-based intervention for slowing lesion accrual.

Cognitive reserve, developed and formalised by Yaakov Stern building on earlier brain-reserve work (Katzman and colleagues, late 1980s), refers to the brain's functional adaptability — built through education, complex work, multilingualism, and lifelong learning. It is distinguished from brain reserve, the structural or biological capacity often operationalised via measures of brain integrity and size. Higher cognitive reserve is associated with better cognitive outcomes for a given level of pathology. In longevity science, it is a central modifiable target of brain-health interventions, helping postpone dementia symptoms.

Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease are proteins measured in lumbar puncture samples that reflect core brain pathologies: Aβ42 (and the Aβ42/40 ratio) decreases in CSF as amyloid is sequestered into plaques, while phospho-tau 181 and 217 (p-tau181, p-tau217) and total tau (t-tau) increase with neurofibrillary tangle pathology and neurodegeneration. Together they operationalise the A/T/N (amyloid/tau/neurodegeneration) biomarker framework endorsed by the 2024 Alzheimer's Association diagnostic criteria, enabling biological rather than purely clinical diagnosis. CSF biomarkers show strong concordance with amyloid and tau PET and can detect Alzheimer's pathology 15–20 years before symptomatic onset; their main limitation is the invasiveness of lumbar puncture. Plasma-based equivalents (especially p-tau217) are rapidly maturing and approaching CSF-level diagnostic accuracy.

The default mode network (DMN) is a set of anatomically connected cortical and subcortical regions — including the medial prefrontal cortex, posterior cingulate cortex, precuneus and angular gyri — that are co-activated at rest and deactivate during externally directed tasks, a pattern first described systematically by Raichle and colleagues in 2001. The DMN supports self-referential thought, episodic memory retrieval, mental simulation and social cognition. In normal aging, DMN connectivity and task-related deactivation weaken, correlating with poorer episodic memory and reduced cognitive flexibility. In Alzheimer's disease, the DMN shows disproportionate amyloid-β deposition and atrophy in its core hubs, consistent with its high baseline metabolic activity and tight coupling to the interstitial fluid dynamics that clear Aβ during sleep.

Flow, described by psychologist Mihaly Csikszentmihalyi, is a state of deep absorption in a challenging activity matched to one's skill, accompanied by reduced self-awareness and altered time perception. It is a popular wellbeing concept whose subjective experience is well-documented, while neural correlates remain debated. For longevity it is relevant because regular flow correlates with life satisfaction, sustained engagement, and the kind of meaningful activity that supports cognitive aging.

Fluid vs crystallized intelligence is a distinction within the Cattell-Horn-Carroll (CHC) framework between two broad cognitive factors with divergent lifespan trajectories. Fluid intelligence (Gf) captures novel reasoning, pattern detection, and problem-solving independent of prior knowledge; it relies on working memory, processing speed, and the frontoparietal network. Crystallized intelligence (Gc) denotes accumulated verbal knowledge, semantic memory, and culturally acquired expertise. Horn and Cattell (1967), studying 297 participants across five age bands (14–61), provided the canonical demonstration: Gf peaks in the early-to-mid twenties and declines nearly linearly thereafter, whereas Gc remains stable or grows into the sixth or seventh decade. Salthouse (2010; n up to 4,149) confirmed that fluid measures decline monotonically from early adulthood, while vocabulary and general-information scores increase through the 60s. The Seattle Longitudinal Study found reliable Gf decrements by age 60, reaching roughly one standard deviation below young-adult levels by 81; Gc decline begins reliably around age 74. Mitchell et al. (2023, J Neuroscience; n = 252 fMRI) showed that reduced frontoparietal responsiveness to cognitive demand mediated roughly one-fifth of age-related Gf loss. Preserved Gc supports expertise-dependent decisions in older adults even as fluid reasoning declines. Interventions targeting processing speed or aerobic fitness yield small Gf gains in trials but transfer is inconsistent (as of 2026); individual trajectories vary substantially.

Gait speed — typically assessed over a 4- or 6-metre walk at comfortable pace — is one of the most robust and inexpensive functional biomarkers of systemic aging, integrating muscular strength, balance, cardiorespiratory capacity, and neurological integrity into a single measurement. A large meta-analysis (Studenski et al., JAMA 2011, over 34,000 participants) showed that each 0.1 m/s increase in gait speed was associated with a 12% lower mortality hazard, and gait speed was as informative about survival as age, sex or body-mass index. Slow gait (typically <0.8 m/s) predicts incident dementia, frailty, falls, hospitalisation and mortality independently of leg strength alone, reflecting the broad integrative demands of coordinated locomotion on the central and peripheral nervous system. In clinical geroscience, gait speed is included in the Short Physical Performance Battery (SPPB) and serves as both a diagnostic marker of physical frailty and a sensitive, modifiable outcome for exercise and nutritional interventions.

Hippocampal volume measures the size of the brain region central to memory consolidation and spatial navigation. Atrophy rates vary by cohort and method: meta-analyses report roughly 0.5–1.4 percent per year in cognitively normal controls, accelerating to about 3.5–4 percent per year in Alzheimer's disease. MRI-derived volume serves as an early biomarker of cognitive aging. Aerobic exercise has been shown to preserve or even enlarge it (Erickson et al. 2011, PNAS), while separate lines of evidence link sleep quality and chronic stress to hippocampal structure.

Ikigai is a Japanese concept loosely translated as a sense of purpose or reason for being, encompassing everyday sources of meaning — relationships, routines, small pleasures — as described by Japanese scholars such as Mieko Kamiya. The popular four-circle Venn diagram (what you love / are good at / can be paid for / what the world needs) is not Japanese in origin: it was created by blogger Marc Winn in 2014 by relabeling Andrés Zuzunaga's unrelated 2011 Spanish purpose diagram, and has no documented connection to Okinawa. The underlying construct of life purpose has been linked in observational studies (e.g., Sone et al. 2008, Ohsaki Study) to lower cardiovascular mortality.

Lewy bodies are eosinophilic intraneuronal inclusions composed predominantly of aggregated α-synuclein protein, first described by Friedrich Lewy in 1912 and identified as the defining pathological feature of Parkinson's disease, dementia with Lewy bodies (DLB), and Parkinson's disease dementia. α-Synuclein (encoded by SNCA) is a presynaptic protein involved in dopaminergic vesicle trafficking; under conditions that include genetic mutations or multiplications of SNCA, oxidative stress, impaired autophagy and lysosomal dysfunction, it misfolds and self-assembles into oligomers and then amyloid-like fibrils that propagate between neurons in a prion-like fashion consistent with Braak's staging of Parkinson's pathology. Whether α-synuclein aggregation is the primary driver of neurodegeneration or a consequence of upstream cellular failure is debated, though the discovery of SNCA multiplications causing familial Parkinson's and the toxicity of oligomeric species in cellular models favour a causal role. In DLB — the second most common neurodegenerative dementia — Lewy body pathology produces fluctuating cognition, visual hallucinations, REM sleep behaviour disorder and parkinsonism, often in combination with Alzheimer co-pathology.

Loneliness, the subjective feeling of social disconnection, is now recognised as an independent risk factor for cardiovascular disease, dementia, and early mortality. Meta-analyses by Holt-Lunstad and colleagues found that strong social relationships were associated with ~50% greater odds of survival (2010, PLOS Medicine), and that social isolation, loneliness, and living alone independently raise all-cause mortality risk by roughly 26–32% (2015, Perspectives on Psychological Science) — an effect Holt-Lunstad has compared by analogy to the mortality risk of smoking up to 15 cigarettes a day, a framing later cited in the 2023 US Surgeon General's Advisory on the epidemic of loneliness and isolation. It dysregulates inflammation, sleep, and HPA-axis stress responses. In longevity science, addressing loneliness through community, purpose, and relationships is a primary, evidence-based intervention.

Microglia are the brain's resident innate immune cells, derived from yolk-sac progenitors that colonise the CNS during early embryogenesis and are maintained independently of peripheral monocytes. In their homeostatic state they continuously survey the parenchyma with ramified processes, pruning synapses, clearing apoptotic debris and releasing neurotrophic factors. With age, microglia shift toward a 'primed' or dystrophic state characterised by altered morphology, impaired phagocytosis and heightened inflammatory reactivity to secondary stimuli, contributing to neuroinflammation. In Alzheimer's disease, GWAS hits in genes such as TREM2, CR1 and BIN1 strongly implicate microglial dysfunction in pathogenesis, positioning microglia as both sensors of amyloid and tau pathology and as active modulators of disease progression.

Defined by Petersen's diagnostic criteria (objective cognitive decline on testing, preserved daily functioning, not meeting dementia threshold), mild cognitive impairment exceeds normal aging without impairing independence. Roughly 10 to 15 percent of people with MCI progress to dementia each year in clinic-based cohorts, with lower rates in community samples. In longevity medicine it is a critical intervention window: lifestyle changes, treatment of vascular risk, sleep optimisation, and hearing correction can stabilise or partially reverse symptoms.

Mindfulness is the trained practice of bringing non-judgmental attention to present-moment experience, typically through meditation. Randomised trials show modest but consistent benefits for stress, anxiety, depression, chronic pain, and blood pressure. Some studies have linked long-term mindfulness practice to longer leukocyte telomeres and modestly reduced inflammatory markers, though findings are inconsistent and effect sizes are small. It remains a low-risk adjunct to standard brain-health and cardiometabolic interventions.

The Mini-Mental State Examination (MMSE), introduced by Folstein, Folstein and McHugh in 1975, is a 30-point structured clinical interview assessing orientation, registration, attention/calculation, recall, language and visuoconstructional ability; it can be administered in 5–10 minutes. Scores of 24–30 are typically classified as normal, 18–23 as mild, 10–17 as moderate and below 10 as severe cognitive impairment. The MMSE was historically the dominant dementia screening tool and remains widely used in clinical practice and trials as a tracking measure, but it has well-documented ceiling effects for MCI detection — sensitivity for MCI is low — and scores are substantially affected by education level, language background and sensory impairment. The MoCA has largely superseded it for MCI screening in research settings, while the MMSE retains utility for staging and longitudinal monitoring of established dementia.

The Montreal Cognitive Assessment (MoCA), developed by Ziad Nasreddine and published in 2005, is a 30-point, 10-minute bedside screening tool covering visuospatial/executive function, naming, memory, attention, language, abstraction and orientation. Its sensitivity for detecting mild cognitive impairment (MCI) is substantially higher than the MMSE — approximately 90% in the original validation study (Nasreddine 2005), with a range of 80–100% across populations, versus 18–45% for the MMSE in clinic-based studies — making it the preferred first-line screen for subtle cognitive change. A score of 26 or above is conventionally considered normal, with one point added for fewer than 12 years of education, though this threshold has been debated given that scores are influenced by education, language proficiency and cultural background, requiring local normative data for valid interpretation. The MoCA is a screening instrument, not a diagnostic test; abnormal scores require further neuropsychological assessment.

Neuroinflammation is activation of the brain's innate immune system — principally microglia and astrocytes — by protein aggregates, injury, or sterile aging signals, producing sustained release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and reactive oxygen species. Acutely protective, this response becomes chronic and maladaptive with aging. Microglia shift from homeostatic surveillance to pro-inflammatory activation, losing phagocytic efficiency for amyloid-β clearance; astrocytes undergo reactive gliosis. The NLRP3 inflammasome is a central node: amyloid-β oligomers and tau aggregates activate this cytosolic complex, triggering caspase-1 cleavage and IL-1β secretion. Ising et al. (2019, Nature) showed NLRP3 knockout in a tau mouse model reduced hyperphosphorylation and improved cognition; NLRP3 was activated in post-mortem frontotemporal dementia microglia. Heneka et al. (2015, Lancet Neurology) established neuroinflammation as a third hallmark of Alzheimer's disease, with CSF and serum elevations of IL-1β, TNF-α, and IL-6 in AD patients. Ransohoff (2016, Science) framed the triad: microglial activation, cytokine release, and synaptic injury — protective mediators becoming drivers of neurodegeneration when sustained. Genetic risk converges: TREM2 loss-of-function variants impair phagocytosis; APOE4 biases microglia toward pro-inflammatory states. Whether neuroinflammation causally precedes Alzheimer pathology or is reactive remains contested; NSAID trials failed, and NLRP3 inhibitors show efficacy only in early preclinical models as of 2026.

Neuroplasticity is the brain's lifelong capacity to reorganise its structure and synaptic connections in response to learning, experience, and injury. It underpins memory formation, recovery from stroke, and skill acquisition at any age. For longevity, neuroplasticity is the mechanism by which exercise, novel learning, social engagement, and sleep protect cognitive function and slow age-related decline.

Polyvagal theory, proposed by Stephen Porges in 1995, posits that distinct vagal branches — a phylogenetically newer ventral-vagal complex and an older dorsal vagal pathway — evolved in mammals to support social engagement versus shutdown/freeze responses. It is widely used in trauma therapy and somatic practice, but its comparative-neuroanatomy and evolutionary claims have been substantively challenged in peer-reviewed work (Grossman & Taylor 2007; Grossman 2023), and mainstream neuroscience does not treat it as established. The well-supported finding that vagal tone (HRV) and breathing influence health does not depend on polyvagal theory and should not be conflated with it.

The prefrontal cortex (PFC), comprising Brodmann areas 9, 10, 11, 46, and 47 and related regions, is the cortical seat of executive function, working memory, cognitive flexibility, impulse control and prospective planning. It is among the latest brain regions to fully myelinate in adolescence and among the earliest to show measurable structural and functional decline with age: cortical thinning, dendritic retraction, reduced dendritic spine density and diminished dopaminergic and noradrenergic signalling accumulate from the fourth decade onward, even in the absence of overt pathology. Functional MRI studies show that older adults recruit PFC more bilaterally and diffusely than young adults performing equivalent tasks — a pattern interpreted as compensatory in some frameworks and as inefficiency in others. PFC age-related decline is accelerated by chronic stress (via glucocorticoid-mediated dendritic remodelling), hypertension and sleep disruption, and is modifiable through aerobic exercise, cognitively demanding activities and adequate sleep.

Presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are nine-transmembrane proteins that form the catalytic core of the gamma-secretase complex together with nicastrin, APH-1 and PEN-2. Gamma-secretase performs intramembrane proteolysis of more than ninety substrates, including the amyloid precursor protein, Notch, N-cadherin and ErbB4. PSEN1 mutations are the most common cause of autosomal-dominant early-onset Alzheimer disease, typically with onset before age 60; more than three hundred pathogenic PSEN1 variants have been reported, most of which shift gamma-secretase cleavage toward longer, more amyloidogenic Abeta42 and Abeta43 species. PSEN2 mutations are rarer and usually associated with later, more variable onset. Carrier families have been pivotal for biomarker timelines through cohorts such as DIAN and the Colombian paisa kindred. The amyloid cascade hypothesis that this biology underpins gained renewed clinical relevance with the approval of lecanemab (FDA 2023, EU 2025) and donanemab (FDA 2024, EU 2025) for early symptomatic Alzheimer disease.

Synaptic plasticity is the activity-dependent change in synaptic strength considered the cellular substrate of learning and memory. The cardinal form is long-term potentiation (LTP), first reported by Bliss and Lomo in 1973 in the dentate gyrus of the rabbit hippocampus after high-frequency stimulation of the perforant path. Hippocampal LTP is typically NMDA receptor dependent: postsynaptic depolarisation relieves the magnesium block of NMDA receptors, calcium entry activates CaMKII, and AMPA receptors are inserted at the postsynaptic density, increasing synaptic gain. Long-term depression, structural remodelling of dendritic spines and metaplasticity provide complementary mechanisms. NMDA receptor dependent LTP declines with age in rodents and is impaired by amyloid-beta oligomers, linking plasticity loss mechanistically to Alzheimer disease symptoms.

Tau is a microtubule-associated protein that under normal conditions stabilises the axonal cytoskeleton by binding to tubulin; in Alzheimer's disease and other tauopathies it becomes hyperphosphorylated, detaches from microtubules, and aggregates into paired helical filaments that form insoluble neurofibrillary tangles (NFTs) inside neurons. The Braak staging system (stages I–VI) tracks the hierarchical spread of NFTs from the entorhinal cortex through the hippocampus to association neocortex, and this progression correlates more tightly with cognitive severity than amyloid plaque burden does. Tau accumulation is thought to disrupt axonal transport, impair synaptic function, and ultimately trigger neurodegeneration, making tau the primary candidate for the neurotoxic effector of Alzheimer's pathology in current models that position amyloid upstream and tau downstream. Tau biomarkers — particularly phospho-tau 181 and 217 in CSF and plasma — have become key diagnostic targets in the AT(N) biomarker framework.

TREM2 (triggering receptor expressed on myeloid cells 2) is a single-pass transmembrane receptor expressed almost exclusively by microglia in the brain. It senses anionic lipids, apolipoproteins and amyloid-beta, signalling through the adaptor DAP12 to drive a transcriptional shift from homeostatic microglia toward the disease-associated microglia (DAM) state, with downstream effects on phagocytosis, lipid metabolism, survival and plaque containment. The rare missense variant R47H (rs75932628) is associated with an approximately 2- to 3-fold increased risk of late-onset Alzheimer disease in pooled analyses, and homozygous loss-of-function variants cause Nasu-Hakola disease. Soluble TREM2 in cerebrospinal fluid is being explored as a biomarker of microglial activation; TREM2 agonist antibodies entered clinical trials, but the lead candidate AL002 (Alector) missed its primary endpoint in the Phase 2 INVOKE-2 trial in early-AD patients in late 2024 and the therapeutic strategy is being reassessed. TREM2 is a key node linking innate immunity to amyloid and tau pathology.

Vascular dementia is cognitive impairment severe enough to disrupt daily function that is attributable to cerebrovascular disease, and is the second most common dementia subtype after Alzheimer disease. Pathological substrates include large-vessel territorial infarcts, lacunes, white-matter hyperintensities, microbleeds and microinfarcts, perivascular space dilation and chronic blood-brain barrier dysfunction, often grouped under the umbrella of small vessel disease. Mixed pathology with Alzheimer-type amyloid and tau is common in older adults and increases cognitive risk for any given burden of either pathology. The VICCCS-2 consensus criteria (2018) operationalise diagnosis across mild and major vascular cognitive impairment, and recognise post-stroke, subcortical ischaemic, multi-infarct and mixed subtypes. Management targets vascular risk factors; no disease-modifying therapy is approved. The Lancet Commission on Dementia Prevention 2024 update (Livingston et al.) raised the modifiable-risk-factor set to 14, adding untreated vision loss and high LDL cholesterol — both directly relevant to vascular cognitive risk.

White matter hyperintensities (WMH) are regions of abnormally high signal intensity on T2-weighted and FLAIR MRI sequences within the cerebral white matter, reflecting focal demyelination, axonal loss, gliosis and small-vessel ischaemia rather than a single pathological entity. Their prevalence rises steeply with age — present in roughly 10–20% of individuals in their 60s and in the majority of those over 80 — and their volume is strongly associated with hypertension, diabetes, and smoking as modifiable risk drivers. WMH predict cognitive decline (particularly processing speed and executive function), incident dementia, stroke and mortality; large or rapidly progressing confluent WMH carry greater clinical weight than small punctate lesions. They are a key imaging marker in the diagnosis of cerebral small vessel disease and in vascular contributions to cognitive impairment and dementia (VCID).